This invention relates to fluidized bed reactors for contacting fluids and solids, such as for carrying out chemical reactions, and particularly relates to processes for cultivating cells, e.g., tissue cultures and fermentations, using such reactors.
Fluidized bed reactors are known in which the fluid is delivered upwardly from the bottom of the reactor through a distribution plate or other resistance which stabilizes the fluidized bed. Stabilization is achieved by virtue of the positive resistance to flow offered by the distribution plate. The distribution plate tends to prevent gross distortion of the flow in the fluidized bed by offering lower resistance in regions having lower fluid velocity, and high resistance in regions of high velocity. Thus, the fluid flow tends to redistribute itself toward uniformity across the cross-section available for flow. A uniform fluid velocity profile is important to avoid channeling and other aberrant flow phenomenon which prevent good solids suspension and good fluid/solid contact. Typical examples of distribution plates known in the art are perforated metal plates, sintered materials, open-cell foams, and beds of pebbles. Fluid may be taken from the top of the fluidized bed and can be recirculated through a pump to the distribution resistance element or plate.
Fluidized bed reactors provide a convenient way for conducting chemical processes which require mass and energy transport between a solid and a liquid or gas. Such reactors potentially offer the advantages of high mass and energy transfer rates over a wide range of throughputs, and have been used in many applications.
In the fermentation-related art, various methods have been devised for immobilizing bioactive materials such as enzymes and microorganisms on or in bead-like supports, referred to herein as biocatalyst beads. Although often quite fragile, these beads generally are suitable for fluidization and thus offer the potential for adaptating fluid bed technology to enzyme catalyzed processes and processes for cultivating cells. There are some problems, however.
Many processes for cultivating cells, such as fermentation processes, employ aerobic microorganisms and cells (in general "organisms"). These organisms demand a continuous supply of oxygen to remain viable. Normally, it is desirable to operate these processes at high solids concentrations, i.e., high cell densities, in order to maximize product yield. Unfortunately, in aerobic processes high cell densities exacerbate oxygen mass transfer demands, which, because of the fragile nature of the biocatalyst beads, cannot be met simply by increasing the level of agitation for increased oxygenation in the bioreactor. Also, in order to operate cell cultivation processes in a continuous manner at optimum conditions, means for controlling the reactor environment, including temperature adjusting means and means for supplying nutrients and other desired reactants to the cell culture and for removing products and by-products (both desirable and undesirable) from the cell culture, must be provided. Control of reactor conditions in this way must be accomplished without sacrificing the aseptic integrity of the system.
Another problem which can be especially acute in continuous cell culture processes utilizing very small biocatalyst beads containing immobilized microorganisms or enzymes is that conventionally designed perforated distribution plates may become plugged by solids or may permit back-flow of biocatalyst beads through the openings, for example, during periods of inactivity. In case of plugging, localized blocking is a typical result. Such blocking causes a change in the hydrodynamic conditions of the fluidized bed upsetting bed stabilization and necessitating that the reactor be shut down for the purpose of cleaning.
Of course, any solution to these problems must take into account the sensitive nature of the biocatalyst beads to physical impact forces and abrasion that might be encountered during operation as well as the sensitive nature of the immobilized bioactive material, especially mammalian cells. In a continuous process, a single charge of biocatalyst beads is expected to have a useful life on the order of six to eighteen months, so long as excessive attrition can be avoided.